Aryl-substituted valeric acids



Patented Mar. 7, 1950 UNITED STATES PATENT OFFICE AR-Ylb-SUBSTITUTEDvVALERIC'" ACIDS James H., Hunter and Jerome Korman, Kalamazoo, Mich;,assignors to The Upjohn Company, Kalamazoo, Mich.,

Michigan a corporation of No Drawing. Application April 30, 1948, SerialNo. 24,413

7 Claims.

wherein R. is selected from. hydrogen and methyl radicals, and wherein Zis selected from cyano, carboxy, and carboikoxy. The number of carbonatoms in the. alkoxy part of the carbalkoxy radicals may be from one toeight, inclusive, representative groupsbeing, for example, carbomethoxy(COOCH3), carbethoxy (--COOC2H5), car- ,bopropoxy (COOC3H.7),carboisopropoxy [COOCH(CI-I3) 2] and the like.

Itis an object of this invention to provide.certainaryl-substituted]valeric acids, esters thereof, and intermediatesuseful in the preparation of the acids and esters, The compounds,areusefjul as chemical intermediates and as therapeuti- Cally-activesubstances.

Itis a. further object of this invention to prepare a-methyl-Ai-di-(p-hydroxyphenyl) valeric acid, having estrcgenic activity.

It is an additional object tov provide a method whereby aa-methyl-a,fi-di(p-hydroxyphenyl)- valeric acid and similararyl-substituted valeric acids may be. prepared.

with an ethylmagnesium halide, preferably the bromide or chloride, inether solution to produce a,fi-di- (p-methoxyphenyl) -valeronitrile.

(b) The nitrile is hydrolyzed with aqueous j alkali, e. g., sodiumhydroxide, toyield diastereoisomeric afl-dl- (p-methoxyphenyl) -valericacid, This acid is esterified by conventional procedure, e. g.,diazomethane, a dialkyl sulfate, et cetera, to give. a lower-alkylafl-di-(p-methoXyphenyD-valerate. The free acid is demethylated, as withpyridine hydrochloride, to yield the a,B-di-(p-hydroxyphenyl) -valericacid, and subsequently esterifi'ed by conventional procedure, e. g.,conversion to the acid chloride and reaction with the selected alcohol,to yieldloweralkyl esters thereof, if desired.

(0) The p-methoxy ester from (b) is methylated using" a metal alkyl, 1.e., triphenylmethyl sodium, andmethyl iodide to yield a lower-alkyl amethyleafi-di' (p-methoxyphenyl') valerate, which is then hydrolyzedwith alkali, e. g., NaOH, KOI-I, to. give diastereoisomerica-methyl-a,'-di- (p-methoxyphenyl)-valeric acid. These isomeric acidsmay be separated by their varying solubilities in butyl alcohol, ifdesired.

(d) The acid from (c) is demethylated, e. g., with pyridinehydrochloride, to give the (Jr-methylafi-di-(p-hydroxyphenyl)-valericacid, which is then reesterified by conventional procedure, e. a,conversion with thionyl chloride to the acid chloride and reaction withalcohol, to produce a loweralkyl a-methyl-afi-di- (p-hydroxyphenyl)-valerate, if desired.

For example, ethylmagnesium bromide and 4,4- dimethoxycyanostilbene werereacted with each other inflbherealsolutiou to produce a,,8'-di(pmethoxyphenyl) -va1eronitri1e. The nitrile was hydrolyzed by. hotaqueous ethyleneglycolic alkali to yield.m,fi.-di-(.p-methoxyphenyl)-valeric acid. The disastereoisomeric acidsthus: produced were separated and the higher-melting isomer esterified.This ester was methylated using triphenylmethyl. sodium (to give thed-SOdiO. derivative) and methyl iodide, and the resulting esterhydrolyzed with. alcoholic alkali to yield a mixture of. isomerica-methyl-a,,8-di-(p.-methoxyphenyl) -valeric, acids, These isomers.were, separated by difiering solubilities in butyl alcohol. The highermelting isomer was demethylat'ed with, pyridine hydrochloride. to giveov-l'IlGthYl efl-di- (pflhydroxyphenyl) -:va1eric acid.

The armethyl.u,B-di- (p-hydroxyphenyll-va1eric acid, when.assayed.by theKahnt-Doisy method employing white rats, produced the full estrousresponse in doses of 20 gamma,

The following examples are illustrative of the present invention but arenot to be constructed as limiting.

Example 1.a,,8-d2'-(xi-methoxyphenyl) valeronitrile To a solution ofethylmagnesium bromide prepared from 4.68 grams of magnesium and 26.5grams of ethyl bromide in 200 milliliters of anhydrous ether was addedin small portions 26.5 grams of 4,4-dimethoxy-a-cyanostilbene [J. Am.Chem. Soc. 64,885 (1942)]. The mixture Was heated under refiux fortwenty-four hours, whereafter it was cooled and the Grignard complexdecomposed with ice and dilute acetic acid. The ethereal layer waswashed with saturated sodium bicarbonate solution, then with water, anddried over sodium sulfate. Removal of the ether gave a viscous red oil.Crystallization of the oil from ethanol gave grams of a,B-di-(pmethoxyphenyl) -valeronitrile, melting at 130-121 degrees centigrade.

Example 2.-u.fl-di-(go-methoxyphenyl) -valeric acid and esters thereof Amixture of 12.1 grams of the nitrile, prepared :as in Example 1, 4.0grams of sodium hydroxide,

8.0 milliliters of water and '75 milliliters of ethylene glycol washeated under reflux for thirty-six hours. Ninety milliliters of waterwas added and the solution filtered while hot. Acidification of thecooled solution with dilute hydrochloric acid yielded a mixture ofisomeric acids.

Recrystallization from ethyl alcohol gave 4.65

grams of an ,,B-di-(p-methoxyphenyl)- valeric acid melting at 177.5-1'79degrees centigrade. On treatment with ethereal diazomethane, the

-methyl ester, melting after crystallization from alcohol at 128.5-130degrees centigrade, was obtained. The ethyl ester is obtained byconversion of the acid to the acid chloride with 80012 and reaction ofethyl alcohol therewith.

The crude residue from the removal of the acid, melting at 177.5-1'79degrees centigrade, after removal of the alcohol, was treated with anethereal solution of diazomethane. After standing two hours, the etherwas removed and the residue crystallized from ethanol to give anisomeric methyl a,}3-di- (p-methoxyphenyl) -valerate melting at 93-945degrees centigrade. Upon saponification, the corresponding acid, meltingat 163-1645 degrees centigrade, was isolated.

Example 3.a-methyZ-u,B-di- (p-methoxyphenyl) -valeric acid and estersthereof In a stoppered flask under a nitrogen atmosphere, a solution of5.0 grams of methyl lLfi-di- (p-methoxyphenyl) -valerate, M. P.128.5-130 degrees centigrade from Example 2, in 50 milliliters of dryether was mixed with 110 milliliters of an ethereal solution containing0.00178 mole of triphenylmethyl sodium. After standing for three hoursat room temperature, 10 milliliters of methyl iodide was added. Theflask was stoppered and allowed to stand overnight. Water and a fewdrops of glacial acetic acid were then added to the reaction mixture.The ethereal layer was separated, the ether removed and the crude methyla-methyl-a, 8 di (p methoxyphenyl) -valerate heated under reflux fortwentytwo hours with a solution of 10 grams of potassium hydroxide in150 milliliters of 95 percent ethyl alcohol. Upon acidification, 4.0grams of mixed isomeric a-methyl-a,fl-di-(p-methoXyphenyl) -valericacids, melting at 165-175 degrees centigrade, was obtained.

A mixture of 1.0 gram of a-methyl-a,c-di-(pmethoxyphenyl) -valeric acid,melting at 181- 1825 degrees centigrade, and 25.0 grams of pyridinehydrochloride was heated at 185-195 degrees centigrade for three hours.After cooling, the mixture was dissolved in water and the aqueoussolution extracted several times with ether. The ethereal extracts werecombined, washed with dilute hydrochloric acid, then with water, anddried. Removal of the solvent gave 0.8 gram ofa-methyl-,;8-di-(p-hydroxyphenyl) valeric acid, melting withdecomposition at 225 degrees centigrade. The methyl, ethyl, and otherloweralkyl esters are obtained by esterifying the free acid byconversion of the acid to the acid chloride and reacting the acidchloride with the desired alcohol.

Various modifications may be made in the present invention withoutdeparting from the spirit or scope thereof, and it is to be understoodthat we limit ourselves only as defined in the appended claims.

We claim:

1. A compound of the formula:

(I)R on wherein R is a member of the group consisting of hydrogen andmethyl radicals.

2. a Methyl-a,p-di(p hydroxyphenyl) -valeric acid.

3. a-Methyl-u, 8-di- (pa-methoxyphenyl) -valeric acid.

4. afi-Di-(p-methoxyphenyl) -valeric acid.

5. In a method for the preparation of a,B-di- (p-methoxyphenyl) -valericacid, the steps of mixing 4,4'-dirnethoxy-a-cyanostilbene with anethylmagnesium halide selected from the group consisting ofethylmagnesium bromide and ethylmagnesium chloride in ether solution:hydrolyzing the resulting a.B-di-(p-methox,vphenyl)- valeronitrile byheating with aqueous alkali; and, isolating a,fi-di-(p-methoxyphenyl)-valeric acid from the reaction product.

6. In a method for the preparation of a-methyla,,8-di-(p-hydroxyphenyl)-valeric acid, the steps of esterifying ap-di-(p-methoxyphenyl) -valericacid; mixing the ester with triphenylmethyl sodium to obtain ana-sodio-a.fi-di-(p-methoxyphenyl) -va.leric acid ester; mixing thesodio-salt with methyl iodide to methylate the a carbon atom;saponifying the ester with alkali; and, demethylating the methoxy groupsto obtain a-methyl-a,e-di-.(p-hydroxyphenyl) -valeric acid.

'7. In a method for the transformation of 4,4- dimethoxy-acyanostilbeneto a-methyl-a,p-di- (p-hydroxyphenyl) -valeric acid, the steps of mixing4,4'-dimethoxy a cyanostilbene with ethy lmagnesium bromid in ethersolution; hy- REFERENCES CITED drolyzing the resulting valeronitrile toa,/3-di- T 1 (p-methoxyphenyl) -va1eric acid by heating with g s ii gggf ii ale of recom m the aqueous alkali; esterifying the carboxy groupof the acid to a carbalkoxy group; methylating the FOREIGN PATENTSa-carbon atom with triphenylmethyl sodium and M methyl iodide;saponifying the ester with alkali; gg a g: 2222 g demethylating themethoxy groups with pyridine hydrochloride; and isolatinga-methy1-a,p-di- OTHER REFERENCES pyd yp acid from the 10 Mentzer et aL,Comptes Rendus (Fr. Acad.), tion product. vol. 215, pages 554-556,(1942) JAMES HUNTER Silverman et al., J. Org. Chem, Vol.11, pp.

JEROME KORMAN. 34439, (1946),

Certificate of Correction Patent No. 2,499,920 March 7, 1950 JAMES H.HUNTER ET AL.

It is hereby certified that errors appear in the printed specificationof the above numbered patent requiring correction as follows:

Column 1, line 19, for carbolkoxy read carbalkoxy radicals; line 38,after the word whereby strike out the letter a; column 3, line 21, formelting at 130-121 read melting at 180-131;

and that the said Letters Patent should be read with these correctionstherein that the same may conform to the record of the case in thePatent Office.

Signed and sealed this 11th day of July, A. D. 1950."

THOMAS F. MURPHY,

Assistant Commissioner of Patents.

1. A COMPOUND OF THE FORMULA;